Breast cancer is the most frequent cancer in women in the United States. A consistent finding in most epidemiological studies has been the protective effect of an early full term pregnancy on the incidence of breast cancer. In animal models the protection afforded by pregnancy can be mimicked by short-term exposure to low doses of estrogens and progestins. The long-term goals of this program project are to understand how steroid hormones are used naturally by the organism to prevent the development of breast cancer. The approach described in this Program Project application is unique as it focuses on a limited exposure of low doses of naturally-occurring hormones to permanently decrease the risk of breast cancer development. The basic model studied in this multi-disciplinary approach is hormone-induced prevention of N-methyl-N-nitrosourea -induced breast cancer in the inbred Wistar-Furth female rat. The Program Project consists of 3 Projects and 4 Core facilities. Project 1 examines the mechanisms of hormonal regulation of p53 and its role as a mediator of hormone- induced resistance to carcinogenesis. Project 2 examines centrosome amplification as a cellular marker for early stages of transformation and its regulation by BTAK, a protein kinase. Project 3 examines specific gene expression, function and localization that is unique to the susceptible and resistant states of the mature mammary gland. Each project is dependent upon the experimental and intellectual contributions of the Core facilities; the Administration/Biostatistics Core, Animal Core, Microscopy and Molecular Cytology Core, and Histopathology Core. The success of this Program Project depends on the complementary expertise provided by the individual investigators in the areas of tumor biology, reproductive biology, developmental biology, molecular endocrinology and molecular biology. The molecular understanding of the fundamental biological events involved in hormone-induced growth and differentiation will provide a rationale for developing new approaches for preventing human breast cancer.